The hollow or tubular geometry of organs has functional significance, such as in the facilitation of fluid or gas transport (e.g., blood, urine, lymph and respiratory gases) or cellular containment (e.g., sperm, ova). Disease processes may affect organs or their components by encroaching upon, obstructing or otherwise reducing the cross-sectional area of the hollow or tubular elements. The ability of the organ to properly function can be severely compromised. An illustrative example of this phenomenon can be seen by reference to coronary vasculature.
Coronary arteries are often subject to attack by disease processes, most commonly by atherosclerosis. In atherosclerosis, the coronary vessels become lined with lesions known as plaques. The development of plaques leads to a decrease in vessel cross-sectional area and a concomitant compromise in blood flow through the vessel. The reduction in blood flow to the coronary muscle can result in clinical angina, unstable angina or myocardial infarction and death.
Historically, the treatment of advanced atherosclerotic vascular disease involved cardio-thoracic surgery in the form of coronary artery bypass grafting (CABG). Such artery bypass grafting is not limited to use with the coronary muscle, but is also used to treat heart and renal failure, arterial aneurysms, and other conditions that require general vascular bypass to restore blood flow to areas of ischemia. Another commonly used method for restoring blood flow to occluded vasculature is percutaneous coronary angioplasty. Angioplasty is a routinely-utilized surgical procedure for the treatment of diseases, such as atherosclerosis and medial arteriosclerosis. Both CABG and angioplasty normally involve injury to a portion of an artery or vein. In many cases the injury is followed by implantation of a donor or synthetic vascular graft, stent, or other implant in order to replace or repair the injured vascular or heart portion.
The treatment of intravascular diseases by angioplasty is relatively non-invasive. Techniques, such as percutaneous transluminal angioplasty (PTA) and percutaneous transluminal coronary angioplasty (PTCA) typically involve use of a guide wire. A typical balloon catheter has an elongate shaft with a balloon attached to its distal end and a manifold attached to the proximal end. In use, the balloon catheter is advanced over the guide wire such that the balloon is positioned adjacent a restriction in a diseased vessel. The balloon is then inflated and the restriction in the vessel is dilated.
Vascular restrictions that have been dilated do not always remain open. In up to 50% of the cases, a new restriction in the lumen of the vascular structure appears over a period of months. The newly formed restriction, or “restenosis,” arises due to the onset and maintenance of intimal hyperplasia at the site of insult. Restenosis and intimal hyperplasia following a procedure on a vascular structure is discussed in the following publications, see, for example Khanolkar, Indian Heart J. 48:281–282 (1996); Ghannem et al., Ann. Cardiol. Angeiol. 45:287–290 (1996); Macander et al., Cathet. Cardiovasc. Diagn. 32:125–131; Strauss et al., J. Am. Coll. Cardiol. 20:1465–1473 (1992); Bowerman et al., Cathet. Cardiovasc. Diagn. 24:248–251 (1991); Moris et al., Am. Heart. J. 131:834–836 (1996); Schomig et al., J. Am. Coll. Cardiol. 23:1053–1060 (1994); Gordon et al., J Am. Coll. Cardiol. 21:1166–1174; and Baim et al., Am. J Cardiol. 71:364–366 (1993).
Intimal hyperplasia also arises in conjunction with vascular reconstructive surgery. Vascular reconstructive surgery involves removing or reinforcing an area of diseased vasculature. Following removal of the diseased portion of the vessel, a prosthetic device, such as an endovascular stent graft or prosthetic graft is implanted at the site of removal. The graft is typically a segment of autologous or heterologous vasculature or, alternatively, it is a synthetic device fabricated from a polymeric material. Stent grafts are generally fabricated from metals, polymers and combinations of these materials. Similar to the situation with angioplasty, intimal hyperplasia also causes failure of implanted prosthetics in vascular reconstructive surgery. Thus, a method to reduce the failure rate for angioplasty and vascular reconstructive surgery by preventing or reducing intimal hyperplasia is an avidly sought goal.
Intimal hyperplasia is the result of a complex series of biological processes initiated by vascular injury followed by platelet aggregation and thrombus formation with a final pathway of smooth muscle cell migration and proliferation and extracellular matrix deposition. Platelets adhere and aggregate at the site of injury and release biologically active substances, the most important of which are platelet-derived growth factors (Scharf et al., Blut 55:1131–1144 (1987)). It has been postulated that intimal hyperplasia production is driven by two principal mechanisms; platelet activation with the release of platelet-derived growth factors, and activation of the coagulation cascade with thrombus formation, which also results in the release of biologically active substances, which can contribute to smooth muscle cell proliferation (Chervu et al., Surg. Gynecol. Obstet. 171:433–447, 1990)).
Attempts to prevent the onset, or to mitigate the effects, of intimal hyperplasia have included, for example, drug therapy with antihyperplastic agents, such as antiplatelet agents (e.g. aspirin, arachidonic acid, prostacyclin), antibodies to platelet-derived growth factors, and antithrombotic agents (e.g. heparin, low molecular weight heparins) (see, Ragosta et al. Circulation 89: 11262–127 (1994)). Clinical trials using antihyperplastic agents, however, have shown little effect on the rate of restenosis (Schwartz, et al., N. Engl. J Med. 318:1714–1719, (1988); Meier, Eur. Heart J. 10 (suppl G):64–68 (1989)). In both angioplasty and vascular reconstructive surgery, drug infusion near the site of stenosis has been proposed as a means to inhibit restenosis. For example, U.S. Pat. No. 5,558,642 to Schweich et al. describes drug delivery devices and methods for delivering pharmacological agents to vessel walls in conjunction with angioplasty.
In addition to simply administering a bioactive agent to a patient to prevent restenosis, a number of more sophisticated methods have been investigated. For example, to address the restenosis problem in vascular reconstruction, it has been proposed to provide stents which are seeded with endothelial cells (Dichek et al, Circulation 80:1347–1353(1989). Both autologous and heterologous cells have been used (see, for example, Williams, U.S. Pat. No. 5,131,907, which issued on Jul. 21, 1992; and Herring, Surgery 84:498–504 (1978)).
Methods of providing therapeutic substances to the vascular wall by means of drug-coated stents have also been proposed. For example, methotrexate and heparin have been incorporated into a cellulose ester stent coating. The drug treated stent, however, failed to show a reduction in restenosis when implanted in porcine coronary arteries (Cox et al., Circulation 84: II71 (1991)). Implanted stents have also been used to carry thrombolytic agents. For example, U.S. Pat. No. 5,163,952 to Froix discloses a thermal memoried expanding plastic stent device, which can be formulated to carry a medicinal agent by utilizing the material of the stent itself as an inert polymeric drug carrier. Pinchuk, in U.S. Pat. No. 5,092,877, discloses a stent of a polymeric material which can be employed with a coating that provides for the delivery of drugs. Ding et al., U.S. Pat. No. 5,837,313 disclose a method of coating an implantable open lattice metallic stent prosthesis with a drug releasing coating.
Other patents which are directed to devices of the class utilizing biodegradable or biosorbable polymers include, for example, Tang et al, U.S. Pat. No. 4,916,193, and MacGregor, U.S. Pat. No. 4,994,071. Sahatjian in U.S. Pat. No. 5,304,121, discloses a coating applied to a stent consisting of a hydrogel polymer and a preselected drug; possible drugs include cell growth inhibitors and heparin. Drugs have also been delivered to the interior of vascular structures by means of a polyurethane coating on a stent. The coating was swelled and a biologically active compound was incorporated within the interstices of the polymer (Lambert, U.S. Pat. No. 5,900,246, which issued May 4, 1999).
The use of stents, as described above, is accompanied by certain disadvantages. For example, in many cases, it is desirable to precondition the structure with anti-hyperplastic agents prior to their undergoing a surgical procedure. As placing a stent requires disrupting the border of the structure in which the stent is to be placed, it is not possible to use a drug-coated stent to precondition a tissue. Moreover, when the drug has diffused out of a drug-loaded stent, it is not possible to administer additional doses of the drug if necessary without replacing the stent and subjecting the repaired structure to additional trauma.
In another method, Edelman et al. have utilized a solid matrix, seeded with vascular endothelial cells (U.S. Pat. No. 5,766,584). The delivery vehicle consists of a three-dimensional matrix onto which endothelial cells are seeded. When the seeded endothelial cells have reached the desired density within the matrix, a vascular structure that has undergone an invasive procedure is wrapped with the seeded matrix. The endothelial cells within the matrix secrete products that diffuse into the surrounding tissue without migrating to the endothelial cell lining of the blood vessel. A procedure that relies on wrapping an injured vascular structure with a delivery matrix is less than ideal. For example, as it is generally desirable for the surgical procedure to be minimally invasive and for the surgical field to be of the smallest possible size, there is a stringent practical limitation the size of the area that can be wrapped and the thickness of the matrix wrapped around the circumference of a vascular structure. Moreover, the endothelial cell-based approaches have not been broadly accepted, because they require that endothelial cell cultures from a patient be established and that the cells be seeded at high densities within the polymeric matrix.
In another method, a modulator of cell or tissue growth is delivered to an extraluminal site adjacent to the point of vascular injury by means of an implanted infusion pump or biodegradable vehicle (Edelman, et al., U.S. Pat. No. 5,527,532). In one embodiment of the Edelman invention, the biodegradable vehicle is implanted in the adventitia at a site adjacent to the site of injury. The modulator is delivered to the adventitia and from the aventitia to exterior surface of the vascular wall.
Neither of the methods disclosed by Edelman et al. address coating directly the exterior surface of a vascular or other tubular structure with a flowable drug delivery matrix into which a therapeutic agent has been dispersed. Moreover, Edelman et al. does not disclose the use of a delivery vehicle that is substantially adherent to the exterior surface of an internal structure of a patient.
A method of preventing or retarding intimal hyperplasia by delivering a therapeutic agent to the site of injury using a drug delivery vehicle implanted on the exterior surface of the injured structure would represent a substantial advance in the art. Moreover, it would be desirable if the method was flexible enough to allow the agents to be applied prior to the surgery and to be reapplied following the surgery. Quite surprisingly, the present invention provides such a method.